According to the World Health Organization obesity has reached epidemic proportions globally, with more than 1 billion adults overweight. At least 300 million of them are clinically obese, and obesity is a major contributor to the global burden of chronic disease and disability. For example, obesity is the most common risk factor for insulin resistance, type 2 Diabetes Mellitus (T2DM) and cardiovascular disorders. Results from the 1999-2002 National Health and Nutrition Examination Survey (NHANES), using measured heights and weights, indicate that an estimated 65 percent of U.S. adults are either overweight or obese. Because millions of adults suffer from obesity or obesity-induced metabolic disorders, new methods for predicting adults at risk for obesity and new compositions for treating obesity and obesity-induced metabolic disorders are in high demand.
Although the detailed molecular events that link obesity with its associated pathologies are not well understood, accumulating evidence suggest that systemic inflammation might be an important mediator (Berg, A. H., and Scherer, P. E., Circ Res, 96:939-949 (2005); Wellen, K. E., and Hotamisligil, G. S., J Clin Invest, 115:1111-1119 (2005)). Studies on both human subjects and animal models have demonstrated a close association between obesity and a state of low-grade, chronic inflammation, which is characterized by macrophage infiltration in adipose tissue and elevated circulating concentrations of pro-inflammatory molecules, including acute phase proteins, cytokines, adiopkines and chemokines (Tataranni, P. A., and Ortega, E., Diabetes, 54:917-927 2005); Cancello, R., et al., Diabetes, 54:2277-2286 (2005); Xu, H., et al., J Clin Invest, 112:1821-1830 (2003); Weisberg, S. P., et al. J Clin Invest, 112:1796-1808 (2003)).
In obese states, pro-inflammatory factors are produced predominantly from enlarged adipocytes and activated macrophages in adipose tissue and liver. Many of these inflammatory factors, such as interleukin (IL) 6, TNFα, resistin and retinol-binding protein 4 (RBP4), can directly induce glucose intolerance and insulin resistance by antagonizing metabolic actions of insulin at peripheral tissues, especially in liver and skeletal muscle (Trayhurn, P., and Wood, I. S. Br J Nutr, 92:347-355 (2004); Fantuzzi, G. J Allergy Clin Immunol, 115:911-919; quiz 920 (2005); Yang, Q., et al, Nature, 436:356-362 (2005)). On the other hand, several other adipokines produced from adipocytes, including adiponectin and visfatin, possess insulin-sensitizing activity and exert beneficial effects on glucose and lipid homeostasis (Kobayashi, K., Curr Drug Targets, 6:525-529 (2005); Kadowaki, T., and Yamauchi, T., Endocr Rev, 26:439-451 (2005); Fukuhara, A., et al., Science, 307:426-430 (2005).
Therefore, it is an object of the invention to provide compositions and methods for assessing the propensity to develop obesity or obesity-induced metabolic disorders.
It is another object to provide compositions and methods for assisting in the diagnosis of obesity or obesity-induced metabolic disorders.
It is still another object to provide methods and compositions for the treatment of obesity or obesity-induced metabolic disorders.
It is another object to provide methods for identifying modulators of lipocalin-2 or a variant thereof.